Stac3 Disorder



Clinical characteristics.

STAC3 disorder is characterized by congenital myopathy, musculoskeletal involvement of the trunk and extremities, feeding difficulties, and delayed motor milestones. Most affected individuals have weakness with myopathic facies, scoliosis, kyphosis or kyphoscoliosis, and contractures. Other common findings are ptosis, abnormalities of the palate (including cleft palate), and short stature. Risk for malignant hyperthermia susceptibility and restrictive lung disease are increased. Intellect is typically normal. Originally described in individuals from the Lumbee Native American tribe (an admixture of Cheraw Indian, English, and African American ancestry) in the state of North Carolina and reported as Native American myopathy, STAC3 disorder has now been identified in numerous other populations worldwide.


The diagnosis of STAC3 disorder is established in a proband with suggestive clinical findings and biallelic pathogenic variants in STAC3 identified by molecular genetic testing.


Treatment of manifestations: At present, no treatment halts or reverses the manifestations of STAC3 disorder. Treatment of musculoskeletal involvement is symptomatic and ideally provided by a multidisciplinary neuromuscular team to address the following:

  • Occupational and physical therapy needs regarding range of motion and mobility
  • Use of adaptive devices for mobility and activities of daily living
  • Feeding difficulties
  • Speech delays
  • Scoliosis
  • Respiratory insufficiency

Due to the medical comorbidities in STAC3 disorder, decisions regarding type and timing of cleft palate surgery should be determined by a multidisciplinary craniofacial team. Depending on the structure of the managing craniofacial team, interventions for ptosis may be undertaken by an ophthalmologist as part of team care, or as an insertion intervention.

Surveillance: Routine monitoring of growth, musculoskeletal complications (e.g., scoliosis and/or joint contractures), speech development, swallowing function, respiratory function, and educational needs.

Agents/circumstances to avoid: Anesthetic agents with a high risk of triggering malignant hyperthermia.

Genetic counseling.

STAC3 disorder is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Unless an individual with STAC3 disorder has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a pathogenic variant in STAC3. Once the STAC3 pathogenic variants have been identified in an affected family member, carrier testing of at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.


Formal diagnostic criteria for STAC3 disorder have not been established.

Suggestive Findings

STAC3 disorder (also known as Native American myopathy) should be suspected in individuals with the following clinical and laboratory findings.

Clinical findings

  • Congenital myopathy
    • Congenital weakness
    • Myopathic facies, characterized by ptosis, inability to raise corners of mouth, and (in some individuals) hollowed-out cheeks from loss of facial musculature, which may cause an open-mouthed expressionless appearance with downturned corners of the mouth. Over time, the face often becomes long and narrow.
  • Musculoskeletal anomalies
    • Congenital contractures ranging from talipes equinovarus (bilateral or unilateral) with or without other joint contractures to arthrogryposis (i.e., multiple contractures of the joints in more than one area of the body present at birth) [Hall 2010]
    • Scoliosis, kyphosis, or kyphoscoliosis
  • Palatal anomalies including cleft palate
  • Micrognathia
  • Characteristic facial features. Myopathic facies, micrognathia, and palatal anomalies can be seen in a number of neuromuscular disorders of varying etiologies; the characteristics that best distinguish STAC3 disorder from other conditions include low-set and/or posteriorly rotated ears, short and/or downslanting palpebral fissures, and telecanthus [Stamm et al 2008a] (see Figure 2: A-I).
  • Short stature
  • Susceptibility to malignant hyperthermia

Laboratory findings. Creatine kinase baseline levels are most often normal [Stewart et al 1988].

Establishing the Diagnosis

The diagnosis of STAC3 disorder is established in a proband with clinical findings consistent with Suggestive Findings and biallelic pathogenic variants in STAC3 identified by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of STAC3 disorder is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of STAC3 disorder has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic findings suggest the diagnosis of STAC3 disorder, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

  • Single-gene testing. Sequence analysis of STAC3 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. Note: To date no large STAC3 deletions or duplications have been identified in individuals reported with molecularly confirmed STAC3 disorder.
    Note: Targeted analysis for the STAC3 pathogenic variant c.851G>C can be performed first in individuals of Lumbee Native American ancestry [Horstick et al 2013].
  • A congenital myopathy multigene panel that includes STAC3 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of STAC3 disorder, some panels for congenital myopathy may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the diagnosis of STAC3 disorder is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. Note: To date no large STAC3 deletions or duplications have been identified in individuals reported with molecularly confirmed STAC3 disorder.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in STAC3 Disorder

Gene 1MethodProportion of Pathogenic Variants 2
Detectable by Method
2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">STAC3Sequence analysis 3All pathogenic variants reported to date 4
Gene-targeted deletion/duplication analysis 5To date no deletions/duplications have been identified.

See Table A. Genes and Databases for chromosome locus and protein.


See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Horstick et al [2013], Grzybowski et al [2017], Telegrafi et al [2017]


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Clinical Characteristics

Clinical Description

STAC3 disorder is characterized by congenital myopathy and musculoskeletal involvement of the trunk and extremities. Most children have weakness with myopathic facies, progressive kyphoscoliosis, and contractures. Other common findings are palatal anomalies (including cleft palate) and short stature. Risks for malignant hyperthermia susceptibility and restrictive lung disease are increased. Intellect is typically normal.

Prior to knowledge of its genetic cause, STAC3 disorder was initially reported as Native American myopathy in an infant from the Lumbee tribe whose findings at birth included arthrogryposis with talipes equinovarus, cleft palate, and micrognathia; at age three months she developed malignant hyperthermia during halothane anesthesia for gastrostomy tube placement due to poor feeding [Bailey & Bloch 1987]. Subsequently 20 additional individuals of Lumbee descent with a clinical diagnosis of Native American myopathy were reported, six by Stewart et al [1988] and 14 by Stamm et al [2008a]. Additional variable findings included ptosis, congenital joint contractures, and scoliosis.

Following the identification of biallelic pathogenic variants in STAC3 in five individuals with Native American myopathy from five families of Lumbee descent by Horstick et al [2013], STAC3 disorder has been confirmed molecularly in another 23 individuals from 15 families of various ancestry: African (5 families), Middle Eastern (4), Puerto Rican (1), Turkish (1), Afro-Caribbean (1), Comoro Islands (1), South American (1), and mixed African and Afro-Caribbean (1) [Grzybowski et al 2017, Telegrafi et al 2017, Zaharieva et al 2018].

The findings of all individuals reported to date with molecularly confirmed STAC3 disorder and clinically diagnosed Native American myopathy are summarized in Table 2 and discussed in more detail in the text that follows the table.

Table 2.

Clinical Findings in Individuals with STAC3 Disorder

2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">FindingLumbee 1
Non-Lumbee 2 (n=23)Total (n=44)
4" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">Congenital myopathyHypotonia21/2120/20 (3 not recorded)41/41
Myopathic facies21/2123/2344/44
Ptosis14/16 (5 not recorded)19/2333/39
Poor feeding11/17 (4 not recorded)18/2329/40
2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">Musculo-
Congenital contractures17/20 (1 not recorded)18/2335/43
Scoliosis, kyphosis, or kyphoscoliosis15/16 (5 not recorded)16/2331/39
2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Short stature6/6 (not recorded 3)13/2319/29
2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Palate anomalies (cleft palate, high-arched palate, or bifid uvula)21/21 (16 w/cleft palate)15/23 (9 w/cleft palate)36/44 total (25/44 w/cleft palate)
2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Malignant hyperthermia7/2112/2319/44
2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Respiratory impairment5/6 (not recorded 4)11/2316/29
2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Cryptorchidism6/8 males7/13 males13/21 males

Bailey & Bloch [1987] (n=1), Stewart et al [1988] (n=6), Stamm et al [2008a] (n=14). The five individuals of Lumbee descent with molecularly confirmed STAC3 disorder reported in Horstick et al [2013] were previously described in Stamm et al [2008a].


Grzybowski et al [2017] (n=1), Telegrafi et al [2017] (n=4), Zaharieva et al [2018] (n=18). All of these cases were molecularly confirmed.


6/6 patients in Stewart et at [1988] had short stature; 2/2 adults in Stamm et al [2008a] had short stature (not included in tally); information was incomplete on all other individuals in Bailey & Bloch [1987] and Stamm et al [2008a].


At least two individuals in Stamm et al [2008a] had respiratory findings (not included in tally); information was incomplete on additional individuals.

Congenital myopathy. The congenital myopathy is slowly progressive with myopathic facies. Deep tendon reflexes in the upper and lower extremities are often decreased or absent. Strength is often decreased in facial, axial, and proximal limb muscles, and may be decreased in distal limb muscles. Examination of older affected individuals may reveal muscle wasting.

Motor delays are most often present by infancy or very early childhood. The maximum motor ability in 15 individuals old enough for evaluation was walking (11), short walk (2), running (1), and sitting independently (1) [Zaharieva et al 2018]. Some affected individuals may be wheelchair bound by adolescence.

Feeding problems. Poor feeding may be due to a combination of structural differences (e.g., cleft palate or high-arched palate, micrognathia) and functional differences (e.g., weak suck, impaired coordination of feeding, abnormal tongue movements, respiratory insufficiency). Descending aspiration may also contribute to feeding and respiratory difficulties. Children with micrognathia and cleft palate may be at increased risk for respiratory issues during feeding (see Management).

Ptosis refers to downward placement (i.e., drooping) of the upper eyelids. In children, ptosis that obstructs the pupil may result in vision impairment or amblyopia. Ptosis may also cause loss of peripheral vision and blurred vision. To maximize vision individuals with ptosis may assume a posture with head tilted backwards and chin pointed upwards.

Musculoskeletal. Congenital contractures can involve the fingers (camptodactyly), hands, wrists, elbows, hips, knees, or feet/ankles (talipes equinovarus). The severity and functional disability range from mild to severe and depend on the joint involved.

Joint laxity has been seen in individuals with or without contractures.

Spinal involvement, including scoliosis, kyphosis, or kyphoscoliosis, is often present by early childhood and is often progressive.

Short stature. Adult height is commonly below the third percentile. Birth length is most often normal.

Speech impairments. Speech development is typically abnormal and dysarthria is common. Factors that can contribute to speech issues in children with STAC3 disorder include the following (see also Management):

  • Abnormal palatal formation, including cleft palate
  • Abnormal tongue movement
  • Compensatory misarticulation
  • Velopharyngeal insufficiency
  • Neurologic factors
  • Atypical resonance
  • Respiratory insufficiency
  • Apraxia

Malignant hyperthermia (MH). All individuals with a reported history of MH survived. Of the cases in which details were provided, most individuals were treated by discontinuing the anesthetic and surgery, and administering dantrolene [Bailey & Bloch 1987, Stamm et al 2008a].

Although MH has been reported in a significant number of individuals, the true frequency of MH susceptibility is likely higher as not all reported individuals had prior surgery or had been exposed to an MH-provoking anesthetic.

Respiratory impairment. Respiratory insufficiency may present in early childhood, late childhood, or adulthood [Stamm et al 2008a, Telegrafi et al 2017, Zaharieva et al 2018].

Other. The majority of affected individuals have normal intelligence; mild intellectual disability is rare [Stewart et al 1988, Stamm et al 2008a].

Conductive hearing loss is common.

Facial hemangiomas may also be present.

Life expectancy. Thirty-six percent of individuals affected with STAC3 disorder died by age 18 years [Horstick et al 2013]. In a study of 14 affected individuals, three died during the first year of life, one from severe pulmonary hypoplasia and one from apnea secondary to enterococcal pneumonia [Stamm et al 2008a].

Muscle findings. Muscle biopsy reveals variable findings:

  • Light microscopy. Small type I and II fibers in some individuals and fiber-type disproportion in others. Increased numbers of central nuclei may be seen.
  • Electron microscopy. An increase in lipid droplets and/or subsarcolemmal mitochondrial accumulations

Electromyogram revealed normal results in some individuals and evidence of myopathy in others [Stewart et al 1988, Stamm et al 2008a].

Genotype-Phenotype Correlations

To date no genotype-phenotype correlations are known.


STAC3 disorder was originally identified in individuals of the Lumbee Native American tribe, which is recognized by the state of North Carolina and has approximately 60,000 enrolled members. The ancestry of Lumbee Native Americans is a mixture of Cheraw Indian, English, and African American [Stamm et al 2008b]. A founder pathogenic variant has been identified in this population (see Molecular Genetics). It is estimated that one in 5,000 Lumbee Native Americans has STAC3 disorder.

See Clinical Description for other populations in which STAC3 disorder has been observed.

Differential Diagnosis

Table 3.

Disorders with Facial Weakness and Hypotonia to Consider in the Differential Diagnosis of STAC3 Disorder

2" scope="col" colspan="1" headers="hd_h_stac3-dis.T.disorders_with_facial_weakne_1_1_1_1" style="text-align:left;vertical-align:middle;">DiffDx Disorder2" scope="col" colspan="1" headers="hd_h_stac3-dis.T.disorders_with_facial_weakne_1_1_1_2" style="text-align:left;vertical-align:middle;">Gene(s)2" scope="col" colspan="1" headers="hd_h_stac3-dis.T.disorders_with_facial_weakne_1_1_1_3" style="text-align:left;vertical-align:middle;">MOI2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Additional Clinical Features of DiffDx Disorder
Overlapping w/STAC3 DisorderDistinguishing from STAC3 Disorder
Central core disease (OMIM 117000)4" colspan="1" style="text-align:left;vertical-align:middle;">RYR1AD
4" colspan="1" style="text-align:left;vertical-align:middle;">
  • Respiratory insufficiency
  • Contractures
  • Arthrogryposis
  • Susceptibility to MH
4" colspan="1" style="text-align:left;vertical-align:middle;">
  • External ophthalmoplegia may be present.
  • Serum CK may be ↑ in King-Denborough syndrome.
RYR1-related congenital fiber-type disproportionAR
RYR1-related multiminicore diseaseAR
RYR1-related King-Denborough syndrome 1 (See Malignant Hyperthermia Susceptibility.)AD
Carey Fineman Ziter syndrome 2 (OMIM 254940)MYMKAR
  • Upturned/broad nasal tip
  • Micro/retrognathia
  • Generalized muscle hypoplasia
  • Delayed motor milestones
  • Normal cognition
No susceptibility to MH documented to date
Moebius syndrome 3 (OMIM 157900)Unknown etiology
in most
cases 4
in most
AD in
small # of
persons 4
  • Cleft palate
  • Talipes equinovarus
  • Short stature
  • Scoliosis
  • Joint contractures
  • Impairment in ocular abduction is obligatory.
  • Variably present:
    • Cranial nerve abnormalities
    • Hearing loss
    • Poland anomaly
    • Limb reduction defects
    • DD, ASD

AD = autosomal dominant; AR = autosomal recessive; ASD = autism spectrum disorder; DD = developmental delay; DiffDx = differential diagnosis; MH = malignant hyperthermia; MOI = mode of inheritance; XL = X-linked


King & Denborough [1973], D'Arcy et al [2008], Dowling et al [2011]


Carey et al [1982], Di Gioia et al [2017], Telegrafi et al [2017], Alrohaif et al [2018], Hedberg-Oldfors et al [2018]


Moebius syndrome was defined by the Moebius Syndrome Foundation Research Conference with the minimum criteria of congenital, nonprogressive facial weakness with limited abduction of one or both eyes [Miller 2007].


Both genetic and environmental etiologies have been proposed. Additionally, prenatal exposure to misoprostol and other agents has been known to cause a Moebius syndrome phenotype.


Heterozygous de novo pathogenic variants in PLXND1 and REV3L have been described in a small number of individuals with congenital facial weakness associated with a variety of additional findings that overlap the Moebius syndrome spectrum [Tomas-Roca et al 2015].


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with STAC3 disorder, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with STAC3 Disorder

ConstitutionalMeasure height, weight, head circumference.Assess for evidence of failure to thrive.
2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">NeuromuscularRefer to pediatric or adult neurologist.Assess severity of muscle weakness.
Refer to neuromuscular clinic incl physical medicine & rehab / PT / OT eval.Assess need for PT &/or OT & adaptive equipment.
MusculoskeletalOrthopedic / physical medicine & rehab / PT / OT eval in multidisciplinary neuromuscular clinicAssess for kyphoscoliosis, talipes deformities, & joint contractures.
PtosisRefer to pediatric or adult ophthalmologist; may be part of craniofacial team.Assess extraocular movements, visual acuity, & visual field.
Feeding issuesRefer to speech therapist, OT, nutritionist, or multidisciplinary craniofacial team.Evals may incl:
  • Physical exam
  • Clinical feeding eval using different types of nipples
  • Video fluoroscopic swallow study
  • Lab eval (e.g., total carbon dioxide level)
  • Chest x-ray
  • Upper GI series
Palatal anomalies
incl cleft palate
Refer to multidisciplinary craniofacial team.Team will assess effect of palatal anomalies on feeding, speech development, & need for surgical interventions.
RespiratoryRefer to pulmonologist.
  • Polysomnography needed to evaluate for central &/or obstructive sleep apnea as well as hypoxia
  • Spirometry + measurement of maximal inspiratory & expiratory pressures & cough peak flow
  • For older children & adults, pulmonary function tests may be helpful.
  • If concern for ascending or descending microaspiration, evaluate for chronic lung disease.
  • Severely affected infants should be evaluated for pulmonary hypoplasia.
2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">Miscellaneous/
Consultation w/clinical geneticist &/or genetic counselorReview natural history of disorder, MOI, recurrence risk, & prognosis.
Obtain surgical history.Evaluate for evidence of MH.

GI = gastrointestinal; MH = malignant hyperthermia; MOI = mode of inheritance; OT = occupational therapist/therapy; PT = physical therapist/therapy

Treatment of Manifestations

At present, no treatment halts or reverses the manifestations of STAC3 disorder; treatment involves reducing symptoms and preventing secondary complications (see Table 5).

Table 5.

Treatment of Manifestations in Individuals with STAC3 Disorder

OT & PTConsider use of adaptive devices to improve mobility.
  • PT to improve range of motion;
  • Stretching, night splints, or serial casts.
Avoid periods of prolonged immobilization (e.g., following surgery).
Per recommendations of treating orthopedistSerial casting, splinting, & surgical intervention may be required.